The overall goal of this research proposal is to optimize the design, composition and formulation of malaria Modular Chimeric Vaccines (MCVs) as effective intervention measures to control the disease in endemic areas. MCVs are synthetic genes designed to express an array of protective antigens derived from several proteins and a number of Plasmodium universal T cell epitopes. Malaria universal T cell epitopes will promote helper T-cell responses, overcome the genetic restriction associated with several malaria antigens and facilitate the boosting effect induced by natural exposure to malaria parasites. MCVs will be designed in silico using computer-assisted algorithms to predict molecular conformation and stability characteristics and to induce immune responses to several stages of the parasite life cycle. The amino acid sequences of these chimeric constructs will be reverse translated, codon optimized and assembled into synthetic genes. The synthetic genes will be cloned, inserted into E. coli, and the proteins expressed and purified. These antigens will be assessed for molecular stability and antigenicity, and then tested for immunogenicity and protection. The first specific aim will focus on developing strategies to construct and deliver stable and efficacious MCVs that can protect rhesus macaques against the experimental challenge with a simian malaria parasite Plasmodium cynomolgi. This parasite reproduces in rhesus monkeys several clinical features of the infection of humans with P. vivax. The second aim of the project will build on the experience gained to design MCVs with the potential to protect humans against P. vivax. These P. vivax MCVs will be tested for immunogenicity and protection in Aotus monkeys, a non-human primate model considered the gold standard for testing malaria vaccine candidates. Our rigorous evaluation of MCVs in stringent models of protection will provide critical data to advance the development of this vaccine platform for use in clinical trials. Relevance. Malaria caused by P. vivax is a major worldwide health problem with an estimated 80 million cases annually. Outside Africa, P. vivax is the most widely distributed malaria parasite. P. vivax malaria is resurging and now represents a serious threat in areas where it had been eradicated. The emergence of P. vivax chloroquine and primaquine drug resistant strains has brought increased emphasis to the need for alternative prophylactic and therapeutic strategies to control this infection.